The studies proposed in this application are directed to characterization of cellular damage induced by shock and trauma, specifically hypovolemic and endotoxic shock and tissue ischemia. The emphasis of the research is directed to mitochondrial alterations and parallel ionic, redox and other cellular alterations possibly contributing, or secondary to the mitochondrial alterations. Primary and secondary defects are being sought. Point of irreversibility is being investigated at the cellular level. The second part of the project involves studies on the adaptation of mitochondrial enzyme systems to altered tissue oxygenation. The mechanism of these adaptations is being investigated as well as the possible tissue alterations contributing to the mitochondrial response.